One of the most well-known and widely used class of antibacterial agents are the so-called beta-lactam antibiotics. These compounds are characterized in that they have a nucleus consisting of a 2-azetidinone (beta-lactam) ring fused to either a thiazolidine or a dihydro-1,3-thiazine ring. When the nucleus contains a thiazolidine ring, the compounds are usually referred to generically as penicillins, whereas when the nucleus contains a dihydrothiazine ring, the compounds are referred to as cephalosporins. Typical examples of penicillins which are commonly used in clinical practice are benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V), ampicillin and carbenicillin; typical examples of common cephalosporins are cephalothin, cephalexin and cefazolin.
However, despite the wide use and wide acceptance of the beta-lactam antibiotics as valuable chemotherapeutic agents, they suffer from the major drawback that certain members are not active against certain microorganisms. It is thought that in many instances this resistance of a particular microorganism to a given beta-lactam antibiotic results because the microorganism produces a beta-lactamase. The latter substances are enzymes which cleave the beta-lactam ring of penicillins and cephalosporins to give products which are devoid of antibacterial activity. However, certain substances have the ability to inhibit beta-lactamases, and when a beta-lactamase inhibitor is used in combination with a penicillin or cephalosporin it can increase or enhance the antibacterial effectiveness of the penicillin or cephalosporin against certain beta-lactamase producing microorganisms. It is considered that there is an enhancement of antibacterial effectiveness when the antibacterial activity of a combination of a beta-lactamase inhibiting substance and a beta-lactam antibiotic is significantly greater than the sum of the antibacterial activities of the individual components against beta-lactamase producing microorganisms.
The present invention relates to salts of 6-alpha-(aminomethyl)penicillanic acid 1,1-dioxide esters readily hydrolyzable in vivo and the prodrug 6-(4-phenyl-2,2-dimethyl-5-oxoimidazolidin-1-yl)penicillanic acid (hetacillin) and the prodrug 6-(4-p-hydroxyphenyl-2,2-dimethyl-5-oxoimidazolidin-1-yl)penicillanic acid.
The invention further relates to salt combinations of 6-alpha-(aminomethyl)penicillanic acid 1,1-dioxide esters readily hydrolyzable in vivo, ampicillin or amoxicillin and a dibasic acid.
These salts are especially useful in providing orally absorbable prodrug forms of 6-alpha-(aminomethyl)penicillanic acid 1,1-dioxide and the appropriate beta-lactam antibiotic.
Pharmaceutical compositions comprising the above-mentioned salts as well as a method for increasing the oral effectiveness of certain beta-lactam antibiotics by the use of such salts are also part of the present invention.
Co-pending U.S. patent application Ser. No. 434,371, filed Oct. 21, 1982 discloses compounds of the formulae ##STR1## and ##STR2## wherein R.sub.1 is hydrogen or a conventional ester forming radical which is hydrolyzable under physiological conditions as beta-lactamase inhibitors useful in combination with active beta-lactam antibiotics.
Other compounds previously reported as beta-lactamase inhibitors useful in combination with beta-lactam antibiotics for the treatment of bacterial infections include penicillanic acid 1,1-dioxide and esters thereof readily hydrolyzable in vivo (Barth, U.S. Pat. No. 4,234,579); the bis-methanediol ester of sulbactam (Bigham, U.S. Pat. No. 4,309,347); various 6-beta-(hydroxymethyl)penicillanic acid 1,1-dioxides and esters thereof (Kellogg, U.S. Pat. No. 4,287,181); and 6-beta-(aminomethyl)penicillanic acid (McCombie, U.S. Pat. No. 4,237,051). Talampicillin (USAN generic name), the 1H-isobenzofuran-3-on-1-yl ester of ampicillin (Clayton et al., J. Med. Chem., 19, pp. 1385-1390, 1976), and (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester of ampicillin (Sakamoto et al., U.S. Pat. No. 4,342,693) exemplify those in vivo hydrolyzable ester radicals of particular interest in the present case. Above cited Clayton et al. also illustrates various crotonolactonyl and butyrolactonyl esters of ampicillin as in vivo hydrolyzable esters.
U.K. patent application No. 2,053,220, published Feb. 4, 1981, broadly discloses beta-lactamase inhibiting compounds of the formula ##STR3## The definitions of R.sub.a, R.sub.b and R.sub.c define literally an infinite number of compounds. These definitions, by appropriate selection of R.sub.a, R.sub.b and R.sub.c, may possibly define the 6-alpha-(aminomethyl)penicillanic acid 1,1-dioxides of present interest. No specific method for preparation of these compounds is present in the disclosure of this U.K. application, and there is no hint or suggestion that from among the infinity of compounds proposed, the present aminomethyl compounds are preferred compounds, possessing the particularly highly potent beta-lactamase inhibitory activity.
Recently, U.S. Pat. No. 4,446,144 disclosed salts between certain 6-beta-halopenicillanic acids and beta-lactam antibiotics or prodrug forms thereof.